Sildenafil Citrate

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 50090-5906

Application: ANDA206401

Effective: 20231124

1 INDICATIONS AND USAGE Sildenafil citrate is indicated for the treatment of erectile dysfunction. Sildenafil citrate is a phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) ( 1 )

2 DOSAGE AND ADMINISTRATION For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity ( 2.1 ) Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg ( 2.1 ) Maximum recommended dosing frequency is once per day ( 2.1 ) 2.1 Dosage Information For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity. The maximum recommended dosing frequency is once per day. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food Sildenafil tablets may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations Sildenafil citrate was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [ see Contraindications ( 4.1 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 ) ] . When sildenafil tablets are co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil tablets treatment and sildenafil tablets should be initiated at 25 mg [ see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.2 ), and Clinical Pharmacology ( 12.2 ) ]. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [ see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7.4 ), and Clinical Pharmacology ( 12.3 ) ]. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [ see Drug Interactions ( 7.4 ) and Clinical Pharmacology ( 12.3 ) ]. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of sildenafil tablets in these patients resulted in higher plasma levels of sildenafil [ see Use in Specific Populations ( 8.5 , 8.6 , 8.7 ) and Clinical Pharmacology ( 12.3 ) ] .

4 CONTRAINDICATIONS Administration of sildenafil tablets to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. Sildenafil citrate was shown to potentiate the hypotensive effect of nitrates ( 4.1 , 7.1 , 12.2 ) Known hypersensitivity to sildenafil or any component of tablet ( 4.2 ) Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4.3 ) 4.1 Nitrates Consistent with its known effects on the nitric oxide/cGMP pathway [ see Clinical Pharmacology ( 12.1 , 12.2 ) ], sildenafil citrate was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated. After patients have taken sildenafil tablets, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Dosage and Administration ( 2.3 ), Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.2 ) ]. 4.2 Hypersensitivity Reactions Sildenafil citrate is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil tablets and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [ see Adverse Reactions ( 6.1 ) ] . 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use sildenafil tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including sildenafil citrate, may potentiate the hypotensive effects of GC stimulators.

Not available.

6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Cardiovascular [ see Warnings and Precautions ( 5.1 ) ] Prolonged Erection and Priapism [ see Warnings and Precautions ( 5.2 ) ] Effects on the Eye [ see Warnings and Precautions ( 5.3 ) ] Hearing Loss [ see Warnings and Precautions ( 5.4 ) ] Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [ see Warnings and Precautions ( 5.5 ) ] Adverse Reactions with the Concomitant Use of Ritonavir [ see Warnings and Precautions ( 5.6 ) ] Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [ see Warnings and Precautions ( 5.7 ) ] Effects on Bleeding [ see Warnings and Precautions ( 5.8 ) ] Counseling Patients About Sexually Transmitted Diseases [ see Warnings and Precautions ( 5.9 ) ] The most common adverse reactions reported in clinical trials (≥ 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Most common adverse reactions (≥ 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Sildenafil tablets were administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil tablets (2.5%) was not significantly different from placebo (2.3%). In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed-dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently. Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Fixed-Dose Phase II/III Studies Adverse Reaction 25 mg (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision † 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% † Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil tablets were taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil tablets at least once weekly, and the following adverse reactions were reported: Table 2: Adverse Reactions Reported by ≥2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction Sildenafil Tablets PLACEBO N=734 N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision † 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% † Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil tablets is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy. Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Musculoskeletal : arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia. Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased. Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis. Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes. Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia. Analysis of the safety database from controlled clinical trials showed no apparent difference in adverse reactions in patients taking sildenafil tablets with and without anti-hypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Cardiovascular and cerebrovascular Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of sildenafil tablets. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil tablets without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil tablets and sexual activity. It is not possible to determine whether these events are related directly to sildenafil tablets, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors [ see Warnings and Precautions ( 5.1 ) and Patient Counseling Information ( 17 ) ]. Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminated study of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported in patients who received sildenafil than in those randomized to placebo. The clinical relevance of this finding to men treated with sildenafil tablets for ED is not known. Nervous: seizure, seizure recurrence, anxiety, and transient global amnesia. Respiratory: epistaxis Special senses: Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including sildenafil tablets. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil tablets, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors [ see Warnings and Precautions ( 5.4 ) and Patient Counseling Information ( 17 ) ]. Ocular : diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal edema, retinal vascular disease or bleeding, and vitreous traction/detachment. Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil tablets. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking [ see Warnings and Precautions ( 5.3 ) and Patient Counseling Information ( 17 ) ]. Urogenital: prolonged erection, priapism [ see Warnings and Precautions ( 5.2 ) and Patient Counseling Information ( 17 ) ], and hematuria.